1. Field of the Invention
The present invention relates to methods and apparatus for handling small fluid volumes. (As used herein and throughout the description and claims directed to this invention, the term "fluid" encompasses liquids alone and liquids containing particulate matter of whatever kind but excludes gases.) In particular, the invention relates to an apparatus and method which are utilized to mix small fluid volumes by applying a deformation force to a deformable support for the fluid and causing agitation and mixing of the fluid as it clings to the support during deformation.
The apparatus and method of the present invention have particular application to situations where small sample volumes are utilized and processed. One such example is the clinical laboratory, in which chemical analyzers are used with fluid samples which are added to reagents and mixed in discrete reaction cups. These reaction cups are typically molded plastic about the size and shape of a sewing thimble. Sometimes they are of a special shape to include multiple compartments, viewing windows for optics, or shaped for centrifugation. They are usually loaded by hand into some form of automated mechanism although automatic loaders have been built. Complicated mechanisms have been built to move the cups between different locations so that various operations can be performed as required by the analysis method. At the end of the analysis, they must be carefully removed to prvent spilling of materials which may constitute a biohazard. The volumes of the cups are usually quite large, consisting of hundreds of microliters. Mixing of sample and reagents can be done in several ways: employment of centrifugal forces, turbulence due to hydraulic discharge, magnetic stir bars or mixing blades or paddles which require cleaning between successive samples. Discrete plastic cups have moderately thick walls and have poor thermal conductivity, making rapid temperature equilibration difficult even with waterbaths. Additionally, discrete cups can be relatively expensive costing from one to several cents each.
As will be seen more fully from the description of the invention which follows, the present invention affords a fluid handling system which minimizes, obviates or totally overcomes problems presented by the prior art devices. For example, it is possible to handle very small volumes of fluid, even sample volumes below 50 microliters. The apparatus promotes mixing of the fluid sample within itself or, if mixed with a reagent, without using any external mixer which is in contact with the reaction mixture. Additionally, the system yields an apparatus which promotes good thermal conductivity such that temperature gradients throughout the mixed system are minimized. The system additionally exhibits simple and safe disposal of used materials and facilitates lower costs through the use of disposables and reduced labor costs or machine costs due to the absence of discrete reaction cups.
2. State of the Art
Numerous devices and apparatus have been suggested for fluid handling of relatively small fluid volumes. Those apparatus and methods have utilized various mechanisms for transporting and mixing the fluids. For example, U.S. Pat. No. 3,650,698 described the dispensing of fluid samples and/or reagents onto a film strip containing quantities or spots of dried suspension of reaction intensifying agent, which may contain magnetic particles to promote mixing when subjected to an alternating magnetic field. U.S. Pat. No. 3,854,703 describes a system in which a jet of gas is directed onto a fluid volume resting on a support to cause relative movement between the fluid and the support, thus promoting mixing of the fluid. U.S. Pat. No. 4,265,544 describes a rotary solenoid coupled to a shaft and sample holder to reciprocally move the sample holder and thus promote mixing of the fluid contained therein. U.S. Pat. No. 4,390,499 describes a test package adapted for use with a spinning rotor to increase mixing which includes a sample compartment, and integral cuvette and compartments for prepackaged reagents. The reagents are adapted to be introduced via breakable seals into the sample compartment which contains the sample to be analyzed. The sample and reagents are introduced via another breakable seal into a cuvette. There the mixture is agitated by mechanical means such as a rotating bar or a pulsating diaphragm.